DOSE-RELATED EFFECT OF AFLATOXIN-B1 ON LIVER DRUG-METABOLIZING-ENZYMES IN RABBIT

The effects of chronic administration of aflatoxin B1 (AFB1) on liver drug metabolism enzymes were measured in New Zealand rabbits divided i nto three groups of 5 animals, each receiving over 5 days either arabi c gum or AFB1 in arabic gum at a daily oral dose of 0.05 or 0.10 mg/kg . These treatments did not lead to any lethality in any of the treated groups but the body weight gain was altered. Biochemical exploration of plasma components revealed a dose-dependent hepatotoxicity characte rized by cytolysis and cholestasis. At 0.10 mg/kg/day of AFB1, signifi cant decreases were observed in total liver microsomal cytochrome P450 , several P450-dependent monooxygenase activities, all individual P450 isoenzymes levels analysed by Western-blotting and glutathione S-tran sferase activities. By contrast, at 0.05 mg/kg/day of AFB1, even thoug h total cytochrome P450 was decreased by 30%, only P450 1A1 and 3A6 is oenzymes, and aniline hydroxylation, pentoxyresorufin O-depentylation, aminopyrine, erythromycin, ethylmorphine and dimethylnitrosamine N-de methylations were affected. In the same animal group, the only glutath ione S-transferase accepting CDNB (1-chloro-2,4-dinitrobenzene) as sub strate was decreased by 22%. UDP-glucuronyltransferase accepting p-nit rophenol as substrate was increased in both groups of animals (33-62%) . The mechanisms that could contribute to the observed changes in drug metabolizing enzymes are discussed.